The role of CREB in stress-induced reinstatement

CREB ​​在应激诱导恢复中的作用

• 批准号: 8232158
• 负责人: LISA A BRIAND
• 金额: $ 5.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232158
• 关键词: Acute; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Brain region; Cells; Chronic stress; Cocaine; Cocaine Dependence; Corticotropin-Releasing Hormone; Cyclic AMP-Responsive DNA-Binding Protein; Exhibits; Experimental Designs; Exposure to; Gene Activation; Goals; Grant; Hippocampus (Brain); Human; Hypothalamic structure; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Label; Lead; Molecular; Mus; Mutant Strains Mice; Neurobiology; Neurons; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Public Health; Relapse; Research; Resistance; Rewards; Rodent Model; Role; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Swimming; System; Ventral Tegmental Area; Work; acute stress; classical conditioning; cohort; coping; drug discovery; drug relapse; experience; mutant; neural circuit; neurochemistry; new therapeutic target; preference; response; restraint; restraint stress; stressor

DESCRIPTION (provided by applicant): Although cocaine addiction is a major public health problem, currently no effective pharmacological treatment options exist. With relapse rates estimated at around 40-60%, developing a better understanding of the mechanisms underlying relapse could provide us with the means to develop better treatment options. Stress has been shown to elicit relapse to cocaine seeking in human addicts and reinstatement of drug seeking in animals models; however, the molecular mechanisms by which stress leads to relapse is unknown. Recent work in our lab has demonstrated that cAMP response element binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned place preference using mice with a constitutive deletion of CREB. Currently, it is unclear which aspects of the neural circuitry depend on CREB to drive stress-induced reinstatement of cocaine seeking. Utilizing behavioral, immunohistochemical, and neuropharmacological approaches, this grant aims to examine the role of CREB in stress-induced reinstatement of cocaine conditioned place preference. Initially, we will examine the role of behavioral coping strategies in response to stress will be examined by examining the ability of stressors that do not engage altered behavioral responding in CREB deficient mice to lead to resinstatement of conditioned reward. Additionally, we will examine differences between both naive and cocaine-experienced wildtype and CREB deficient mice in the ability of stress to engage neurobiological circuitry implicated in stress-induced reinstatement. Finally, interactions between CREB and corticotropin-releasing factor (CRF) will be elucidated by local infusions of CRF into the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA) prior to reinstatement. The goal of this research is to gain a better understanding of how stressful experiences can lead to drug relapse. By investigating the role of CREB in both the behavioral responses to stress as well as the molecular mechanisms underlying the interactions between stress and drug seeking we can identify new therapeutic targets for drug discovery

描述（由申请人提供）：虽然可卡因成瘾是一个主要的公共卫生问题，但目前尚无有效的药物治疗选择。复发率估计约为 40-60%，更好地了解复发机制可以为我们提供开发更好治疗方案的方法。研究表明，压力会导致人类成瘾者重新吸食可卡因，并在动物模型中恢复吸毒行为；然而，压力导致复发的分子机制尚不清楚。我们实验室最近的工作表明，使用 CREB ​​组成性缺失的小鼠，cAMP 反应元件结合蛋白 (CREB) 对于应激而非可卡因诱导的条件性位置偏好恢复是必需的。目前，尚不清楚神经回路的哪些方面依赖于 CREB ​​来驱动压力诱导的可卡因寻求恢复。利用行为、免疫组织化学和神经药理学方法，这项资助旨在研究 CREB ​​在应激诱导的可卡因条件性位置偏好恢复中的作用。首先，我们将通过检查应激源的能力来检查行为应对策略在应激反应中的作用，这些应激源不会改变 CREB ​​缺陷小鼠的行为反应，从而导致条件奖励的恢复。此外，我们将检查未接触过可卡因的野生型小鼠和 CREB ​​缺陷型小鼠在压力参与与压力诱导的恢复有关的神经生物学回路的能力方面的差异。最后，CREB ​​和促肾上腺皮质激素释放因子 (CRF) 之间的相互作用将通过在恢复前将 CRF 局部输注到终纹床核 (BNST) 和腹侧被盖区 (VTA) 来阐明。这项研究的目的是更好地了解压力经历如何导致药物复发。通过研究 CREB ​​在压力行为反应中的作用以及压力与药物寻求之间相互作用的分子机制，我们可以确定药物发现的新治疗靶点